Acute ischemic stroke causes irreversible injury in the ischemic core, but reversible injury in the peri- focal zone, the penumbra. Conventional drug delivery methods cause unwanted drug exposure to other tissue or brain regions, leading to severe side effects and toxicity, especially when high dose is being used for reaching therapeutic drug levels in ischemic tissue. With the advancement of CNS drug delivery system, those problems can be tackled through a novel approach. Liposomal nanocarriers facilitate biological membrane penetration, protect drugs from enzymatic/chemical degradation and albumin binding, and minimize drug exposures to non-target tissue. Moreover, they can be optimized to release their cargos under acidic conditions similar to the intracellular microenvironment of ischemic brain tissue (pH<6.75). We have manufactured nanoliposomes that are stable in both neutral pH and pH range 5-6 (typical endosome/lysosome pH range);and the encapsulation efficiency is high enough for drug delivery to ischemic tissue through residual blood flow. These liposomal nanocarriers can be manufactured in different sizes, and be further enhanced for long circulating time by poly(ethylene-glycol) (PEG), for BBB penetration by the trans-activating transcriptional activator (TAT peptide) (Torchilin et al. 2001) and for ischemic tissue selectivity by "CLEVSRKNC" peptide, which is a stroke-homing peptide, stands for the single letter sequence for Cys-Leu-Glu-Val-Ser-Arg-Lys-Asn- Cys (Hong et al. 2008). Therefore, this technique provides a means for targeted intracellular drug delivery into ischemic penumbra. Although ischemia results in many pathological cascades, bioenergy state remains one of the determining factors that control and differentiate ischemic cell death (Leist et al. 1997;Lieberthal et al. 1998). Bioenergy state can be maintained by decreasing energy demand through metabolic suppression and by providing exogenous energy. Penumbra-selective intracellular delivery of a metabolism suppressor and energy current is an attractive strategy for reducing ischemia-induced injury. We hypothesize that optimized multiple- targeted pH-sensitive nanoliposomes can be used for penumbra-selective drug delivery for reducing brain ischemic injury in acute stroke. Here we propose a study to optimize multiple-targeted pH-sensitive nanoliposomes for selective drug delivery to ischemic penumbral tissue, and test the delivery efficiency and neuroprotective effect of drug-loaded pH-sensitive nanoliposomes in acute stroke treatment. PUBLIC HEALTH RELEVANCE: Stroke is one of the leading causes of death and disability in developed countries, but its treatment is very limited. The current drug delivery system for treating ischemic strokes is neither selective for the ischemic brain tissue, nor optimal for passing blood-brain-barrier. Here we propose a study to explore the feasibility of selective drug delivery to the ischemic brain tissue.